Interleukin-4 (IL-4) is a pivotal component in the regulatory network of cytokine which orchestrate immune and inflammatory responses. Activities by this molecule have been implicated in many beneficial immune mechanisms, including protection against parasitic helminth infections. However, IL-4 is best known for the pivotal role it plays in the pathophysiology of atopic diseases. The molecular processes which control cellular expressions of this cytokine remain unresolved, although evidence now implicated the transcription factors STAT6, c-Maf an dNIP45 as being required to promote IL-4 production. We have recently uncovered a novel regulatory pathway involving Neu-1, a sialidase encoded within the Neu-1 locus of the murine MHC. Activities by Neu-1 appear to be necessary for initiating IL-4 gene expression by activated T-cells. Using molecular tools made available from the recent cloning of murine neu-1, we will explore the processes which control Neu-1 gene expression by T-cells, plus the mechanisms which allow this sialidase to modulate production of IL-4. We will investigate the requirement for Neu-1 production by T-cells following activation and also plan to characterize the promoter region of neu-1 to gain information about the transcription factors which control expression of this gene. Modulatory influences by Neu-I on signaling events through the IL-4R, as well as changes in c-Maf and NIP45 expression and activities will be carefully analyzed. We have recently determined that the monosialylated ganglioside GM3 represents a membrane associated target for Neu-1 and could be involved in the regulatory influences by Neu-1 on cytokine production. Influences by GM3 seem to reside upstream of TCR-stimulated calcium signaling, since IL-4 produced in response to ionomycin or thapsigargin exposure is refractory to GM3 regulation. Mechanisms responsible for the counterregulatory influences by GM3, the major ganglioside on T-cell plasma membranes will be explored. How GM3 influences calcium signaling events, as well as its potential to negatively regulate STAT6, C-Maf or NIP45 expression or activities will be studied. Finally, we will evaluate the use of GM3 in vivo, as a strategy to selectively inhibit IgE production in immunized animals.
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